The Role of the Proteasome in Limiting Cellular Stress Associated with Protein Accumulation

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The Role of the Proteasome in Limiting Cellular Stress Associated with Protein Accumulation


Abstract

The proteasome is comprised of multiple subunits that catalyze the degradation of proteins to maintain cellular homeostasis. The proteasome targets protein substrates by two different pathways. The ubiquitin-dependent pathway requires proteins to be labeled with a ubiquitin tag to signal for degradation by the 26S isoform of the proteasome. Protein degradation through this pathway declines during age progression. The ubiquitin-independent pathway utilizes the 20S proteasome isoform. It can degrade misfolded and intrinsically disordered proteins to decrease cellular stress. Age-related protein accumulation and aggregation can occur due to the decreased activity and expression of the proteasome. Protein accumulation causes increased cellular stress which can contribute to disease progression. Increasing proteasome activity could serve as a solution to eliminating and preventing protein accumulation. Studies have shown the value of the proteasome as a therapeutic entity to mitigate cellular stress. This perspective explores the link between proteasome activity and cellular stress caused by age-related misfolded protein accumulation.

Understanding and Overcoming Biochemical Diversity in AL Amyloidosis

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Understanding and Overcoming Biochemical Diversity in AL Amyloidosis


Abstract

Amyloid fibril deposition causes progressive tissue damage and organ failure in the systemic amyloid diseases, and therapies that suppress aggregation lead to clinical benefit. Small molecules that prevent aggregation by binding to precursor proteins are effective for amyloid transthyretin (ATTR) amyloidosis. However, in amyloid light chain (AL) amyloidosis, fibrils are formed by antibody light chains and every patient has a unique protein sequence that aggregates. The highly diverse sequences of these light chains appear to determine whether an individual is at risk of amyloidosis, the distribution of amyloid deposits and the progression of disease. Light chains are therefore challenging drug targets. This review explores the parallels between AL amyloidosis and ATTR amyloidosis to describe the discovery of small molecules that can stabilize light chains. These molecules have potential as therapies for AL amyloidosis, highlighting potential opportunities for drug discovery in other diseases of protein misfolding.